Platinum-based drugs (or “platins”) are effective anticancer drugs, forming DNA adducts that block DNA and RNA synthesis in cancer cells and inducing apoptosis. Cisplatin, carboplatin, and oxaliplatin are the main platins used for treating numerous solid tumors including ovarian, lung, colorectal, testicular, bladder, gastric, melanoma, and head and neck cancers. However, a major disadvantage of the platins is toxicity. Common side effects include kidney and nerve damage, high-end hearing loss, prolonged nausea, and vomiting.
Cisplatin (Cis-PtCl2(NH3)2; shown below as Formula I) was approved by the FDA in 1978 for treatment of a variety of cancers and has been used since then for cancer treatment. Cisplatin exhibits a planar molecular structure, and has a solubility of about 1-2 mg/mL in 0.9% saline at 25-37° C. (8 mg/mL at 65° C.). Cisplatin is given to patients intravenously in saline (sodium chloride solution) and enters the cells by either passive diffusion or other facilitated transport mechanisms. Once inside the cytoplasm, cisplatin undergoes hydrolysis. The chloride ligands are each replaced by a molecule of water, producing a positively charged molecule. Uncharged species are unreactive, but monovalent cations and the divalent cationic species are most reactive.
Cisplatin is a particularly toxic drug. There are several disadvantages associated with use of the drug: a) its severe toxicity such as nephrotoxicity, neurotoxicity and emetogenesis, which is the main dose-limiting factor; b) its rapid excretion via kidneys resulting in a short circulation half life, c) its strong affinity to plasma proteins; and d) its limited aqueous solubility of about 1 mg/mL at room temperature. It is desirable to develop a formulation which will increase the concentration of cisplatin locally at the tumor site. It is also desirable to reduce the accumulation of cisplatin in other tissues to minimize the toxic side effects.

Liposomes have been used as delivery vehicles for platins in an attempt to reduce the drugs' toxicity. A liposome is a vesicle including a phospholipid bilayer separating exterior and interior aqueous phases. Liposomes are capable of carrying both hydrophobic drugs in the lipid bilayer and/or hydrophilic drugs in the aqueous core for drug delivery. Liposome size typically ranges from 50 to 250 nm in diameter, with diameters of 50 to 150 nm being particularly preferable for certain applications. The use of liposomal platins, including cisplatin, has presented considerable challenges. Liposomal platins demonstrate unique patterns of distribution, metabolism, and excretion from the body compared with the free drugs, as well as varying toxicity levels and unique side effects. In particular, optimizing the release rate of liposomal platins is a difficult balancing act between safety and efficacy. In general, leaky liposomes will make the encapsulated drugs more available, but cause more risk in toxicity similar to the native drugs. On the other hand, less leaky liposomes may reduce toxicity, but may not provide sufficient drug release for adequate efficacy.
U.S. Pat. No. 6,126,966 (the '966 patent) describes sterically-stabilized liposomal cisplatin. Specifically, the liposomal composition is described as of a vesicle-forming lipid (e.g., a phosphatidylcholine) with between 1-20 mole % of a vehicle-forming lipid derivative with a hydrophilic polymer having an uncharged cap (e.g., a poly(ethylene gycol)-modified phospholipid), said liposomes being formed such that the hydrophilic polymer forms a coating of hydrophilic polymer chains on both inner and outer surfaces of the liposomes. However, another report included cryo-TEM images of distearoylphosphatidylcholine (DSPC) dispersions containing a poly(ethylene glycol)-distearoylphosphatidylethanolamine (DSPE-PEG5000) at various concentrations (Biophysical Journal Volume 85, December 2003, pages 3839-3847). The images demonstrated mixtures containing as low as 7.1 mol % of DSPE-PEG5000 DSPC were predominantly micelles as opposed to the liposomes claimed in the '966 patent. Moreover, the sterically-stabilized liposomal cisplatin described in the '966 patent demonstrated limited in vivo efficacy in phase II study trials (Feng, et al. Cancer Chemother. Pharmacol. 54: 441-448. 2004). Clearly, liposome structure and physical properties, including in vivo half life and drug release profiles, can not be simply predicted based on the make-up of the liposomes.
Given the shortcomings of known formulations, it is desirable to develop liposomal cisplatin with improved properties compared to existing liposomal and non-liposomal platin therapeutics. There is a need for formulations that balance efficacy and safety and improve the bioavailability of cisplatin to targeted cancer cells. The present invention addresses these and other needs.